Thimerosal, which is approximately 50% mercury by weight, has been one of the most widely used preservatives in vaccines. It is metabolized or degraded to ethylmercury and thiosalicylate. Ethylmercury is an organomercurial that should be distinguished from methylmercury, a related substance that has been the focus of considerable study.
At concentrations found in vaccines, thimerosal meets the requirements for a preservative as set forth by the United States Pharmacopeia; that is, it kills the specified challenge organisms and is able to prevent the growth of the challenge fungi (U.S. Pharmacopeia 2004). Thimerosal in concentrations of 0.001% (1 part in 100,000) to 0.01% (1 part in 10,000) has been shown to be effective in clearing a broad spectrum of pathogens. A vaccine containing 0.01% thimerosal as a preservative contains 50 micrograms of thimerosal per 0.5 mL dose or approximately 25 micrograms of mercury per 0.5 mL dose.
Thimerosal is a mercury-containing organic compound (an organomercurial). Since the 1930s, it has been widely used as a preservative in a number of biological and drug products, including many vaccines, to help prevent potentially life threatening contamination with harmful microbes. Over the past several years, because of an increasing awareness of the theoretical potential for neurotoxicity of even low levels of organomercurials, concerns about the use of thimerosal in vaccines and other products have been raised. Indeed, because of these concerns, the United States Food and Drug Administration (FDA) has worked with, and continues to work with, vaccine manufacturers to reduce or eliminate thimerosal from vaccines.
Thimerosal has been removed from or reduced to trace amounts in all vaccines routinely recommended for children 6 years of age and younger, with the exception of inactivated influenza vaccine. Some vaccines such as Td (tetanus and diphtheria vaccine), which is indicated for older children (≧7 years of age) and adults, are also now available in formulations that are free of thimerosal or contain only trace amounts. Vaccines with trace amounts of thimerosal contain 1 microgram or less of mercury per dose.
The various mercury guidelines are based on epidemiological and laboratory studies of methyl mercury, whereas thimerosal is a derivative of ethyl mercury. Because they are different chemical entities—ethyl- versus methylmercury—different toxicological profiles are expected. There is, therefore, an uncertainty that arises in applying the methylmercury-based guidelines to thimerosal. Lacking definitive data on the comparative toxicities of ethyl- versus methylmercury, the FDA considered ethyl- and methyl-mercury as equivalent in its risk evaluation.
Allergic responses to thimerosal are described in the clinical literature, with these responses manifesting themselves primarily in the form of delayed-type local hypersensitivity reactions, including redness and swelling at the injection site (Cox N H, Forsyth A. Thimerosal allergy and vaccination reactions. Contact Dermatitis 18:229-233, 1988). Such reactions are usually mild and last only a few days.
In 2001, the Institute of Medicine (10M) convened a committee (the Immunization Safety Review Committee) to review selected issues related to immunization safety. One such review focused on a potential relationship between thimerosal use in vaccines and neurodevelopmental disorders (Institute of Medicine, Thimerosal-containing vaccines and neurodevelopmental disorders, Washington D.C.: National Academy Press, 2001). In its report, the 10M's Immunization Safety Review Committee concluded that the evidence was inadequate to either accept or reject a causal relationship between thimerosal exposure from childhood vaccines and the neurodevelopmental disorders of autism, attention deficit hyperactivity disorder (ADHD), and speech or language delay. Additional studies were needed to establish or reject a causal relationship. The Committee did conclude that the hypothesis that exposure to thimerosal-containing vaccines could be associated with neurodevelopmental disorders was biologically plausible.
Therefore there exists a need for methods and systems to easily remove thimerosal from injectable materials at the point of service.
Metallothioneins (MTs) are small metal binding proteins ubiquitously distributed throughout the animal kingdom. They have high metal binding affinities and are believed to be important in controlling the intracellular levels of free metal ions. The structural features of MTs include a high cysteine composition and lack of aromatic amino acids. The cysteine residues are responsible for the protein's high affinity metal binding to heavy metals including arsenic, zinc, copper, cadmium, mercury, cobalt, lead, nickel, chromium, uranium, platinum, gold, silver and their complexes. In general, MTs from divergent species have a high degree of amino acid sequence similarity. If fact, the amino acid residues responsible for metal binding are essentially invariant between species.
Accordingly, an object of the present invention is to provide methods and devices to remove thimerosal from medications and bioactive materials at the time of administration using metallothionein-based systems.